Many functional disorders, including irritable bowel syndrome (IBS), are associated with alterations in the stress response. Since chronic sustained stress often precedes exacerbations of both functional and inflammatory diseases of the intestine, understanding the mechanisms underlying this phenomenon have important implications for therapeutic intervention. Acute psychological or physical stress activates both the sympathetic and parasympathetic branches of the autonomic nervous system (ANS) and the hypothalamic pituitary adrenal (HPA) axis. These systems modulate pain pathways, but also influence the peripheral immune function. Peripherally acting products of the HPA axis (glucocorticoids) and both branches of the ANS (catecholamines and acetylcholine) inhibit peripheral immune function, principally by blocking the action of pro-inflammatory cytokines that stimulate cellular immunity. However, the normal restraining effect of acute stress on immune cell proliferation and activation is compromised during chronic stress by changes in the central stress circuits, including a blunting of the I-IPA axis response, down regulation of certain adrenergic receptors, and decreased vagal tone. The current proposal is based on the general hypothesis that development of hypocortisolism (reduced glucocorticoid secretion) during chronic stress may be an important factor in the up-regulation of the gut-associated immune system, production of inflammatory cytokines and cytokine-mediated sensitization of visceral afferent nerve pathways. In a rat model, we have found that chronic psychological stress leads to profound, long lasting visceral hyperalgesia to mechanical distension of the colon and rectum, associated with mast cell hyperplasia and up-regulation of the pro-inflammatory cytokines, tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6). By exposing rats to a chronic psychological stressor and assessing HPA axis, mucosal immune function and visceral nociceptive responses, we will test this general hypothesis in 3 specific aims. In aim 1, we measure changes HPA axis during and after chronic stress and determine the underlying mechanisms involved in modulating this response. In aim 2 we will correlate these endocrine changes with changes in mucosal immune cell infiltration and activation by enzyme assays, immunohistoehemistry, and quantification of mucosal cytokine mRNA levels. In aim 3, we evaluate 2 specific therapeutic interventions aimed at blocking the central stress response or mucosal immune activation for reduction of visceral hyperalgesia. These proposed experiments should also establish whether chronic psychological stress in rats is a reasonable model of chronic stress mediated symptom exacerbations in IBS patients.